A bacterial toxin may be defined as “a substance which is a bacterial metabolite or constituent and causes, in a trace amount, an unfavorable response in the living body”. Bacterial toxins are roughly classified into two classes, endotoxins and exotoxins, according to the site of occurrence. The former are also called as protein toxins, and the latter as lipopolysaccharides (hereinafter referred to as “LPSs”). There are a large number of bacterial toxins, and the number of such toxins so far known now stands at about 200. Typical examples are cholera toxin, staphylococcal α toxin, botulinum toxin, tetanus toxin, enterotoxin (10 species are already known, namely staphylococcal enterotoxin A, B, C1, C2, C3, D, E, G, H, and I; hereinafter referred to as SEA, SEB, SEC1, SEC2, SEC3, SED, SEE, SEG, SEH, and SEI, respectively), verotoxins, diphtheria toxin, pertussis toxin, Toxic shock syndrome toxin-1 (hereinafter referred to as TSST-1), and endotoxins.
Among these, enterotoxins and TSST-1 are also called as superantigens.
In the case of an ordinary antigen, it is taken up by an antigen-presenting cell and fragmented (into peptides composed of 10 to 15 amino acids) therein, and an antigen fragment, in the form bound to a pocket site of a MHC (major histocompatibility complex) class II molecule, is presented on the antigen-presenting cell surface. This is recognized by the α chain and β chain of the TCR (T cell receptor) of a specific T cell clone, and the T cell is activated and the immune response goes on.
On the other hand, in the case of a superantigen, the antigen is not fragmented but binds directly to a MHC class II molecule on the antigen-presenting cell. This is further recognized by the TCR on a T cell, whereby the T cell is activated. On that occasion, the antigen is recognized through a specific Vβ region of the TCR. Unlike ordinary antigens, that antigen is recognized by almost all members of a T cell population expressing this specific Vβ region, and T cells are thereby activated and causing cytokine production.
Thus, when an individual is exposed to a superantigen, a huge number of T cells are activated as compared with the ordinary specific immune response and the release of a cytokine, for instance, occurs in a short period of time, supposedly causing an abnormal reaction(s) in the living body.
Known as the superantigen are TSST-1, enterotoxins and exfoliative toxin A (exfoliative A: ETA) produced by Staphylococcus aureus, which is a gram-positive bacterium, and exotoxins produced by streptococci (streptococcal pyrogenic exotoxin A, B, C: SPE-A, SPE-B, SPE-C), among others.
An enterotoxin is one of toxins produced by bacteria. It has various biological activities, such as emetic, pyrogenic and mitogenic activities, and causes food poisoning symptoms or Toxic shock syndrome (hereinafter referred to as TSS). “Enterotoxin” is a term formed from “entero”, which means the intestine, and toxin. Although it essentially means a toxin causing diarrhea, it has not yet established that an enterotoxin causes diarrhea; hence what it really means is unclear.
Toxins having enterotoxin activity include toxins having various biological activities, such as emetic, pyrogenic and mitogenic activities, and causing food poisoning symptoms or TSS. Known among them are enterotoxins produced by staphylococci, heat-labile enterotoxin (hereinafter referred to as LT) produced by Campylobacter species, and LT and heat-stable enterotoxin (ST) produced by enterotoxigenic Escherichia coli, among others.
Staphylococci are widely distributed on or in the skin, nasal cavity, oral cavity, pharynx, urinary organs and intestinal tract of various animals including humans and, further, in air, sewage, river, food, and so forth and include a large number of species. Among such a large number of Staphylococcus species, it is coagulase-positive Staphylococcus aureus (hereinafter referred to as S. aureus) that shows pathogenicity in humans. S. aureus causes various infectious diseases, such as TSS and staphylococcal scaled skin syndrome (SSSS) and, as pathogens, producing problems such as hospital infections. Furthermore, Staphylococcus epidermidis, for instance, may cause endocarditis, meningitis, septicemia, etc., and Staphylococcus saprophticus may cause urinary tract infection, although they are coagulase-negative.
Known staphylococcal pathogenic factors include various toxins, enzymes and other biologically active substances, such as Clumping factor, fibrinogen-binding protein, fibrinogen-binding protein A, fibrinogen-binding protein B, collagen-binding protein, coagulase, polysaccaride/adhesin, polysaccaride intracellular adhesin, 220-kDa adhesin, SEA, SEB, SEC1, SEC2, SEC3, SED, SEE, SEG, SEH, SEI, TSST-1, exfoliative toxin A, exfoliative toxin B, protein A, lipase, V8 protease, fatty acid modifying enzyme, panton-valentine leucocidin, leucocidin R, capsular polysaccaride, staphylokinase, α-toxin, β-hemolysin, γ-hemolysin, δ-hemolysin, phospholipase C, metalloprotease (elastase), and hyaluronidase.
These bacterial toxins cause a great variety of diseases, from such relatively slight ones as food poisoning and traveler's diarrhea to such severe ones possibly leading to death as lethal diarrhea, tetanus, pertussis, botulism, diphtheria, cholera, TSS, and septicemia.
In the case of septicemia and TSS, for instance, antibiotics, γ-globulin preparations and so forth are used in the treatment thereof, but the mortality is still high. As for food poisoning, it is difficult to perfectly prevent the occurrence of food poisoning how much care is taken from the hygienic point of view and, further, even when a food sufficiently heated is taken, it may cause food poisoning if a heat-stable toxin, such as an enterotoxin, is already contained therein.
As regards the removal of superantigens by adsorption, Japanese Kokai Publication Hei-8-319431 discloses an adsorbent having a specific side chain. However, this cannot be said to be satisfactory from the capacity viewpoint.
The present inventors have previously found that a material with a compound having a log P value (P being the partition coefficient in the octanol-water system) of not less than 2.50 as immobilized thereon can well adsorb TSST-1 (one of bacterial toxins) (Japanese Kokai Publication Hei-10-290833). For preparing such adsorbent material, however, a number of steps are required.
When, for instance, antibodies specific to various toxins respectively are used, it is indeed possible to remove toxins from body fluids such as blood, plasma and serum, culture supernatants, foodstuffs, and drinks, but these have disadvantages, namely they are expensive and, when sterilized, they are denatured and their absorptive ability is markedly reduced.
As regards endotoxins, various adsorbents are known for removing them from body fluids. For example, Japanese Kokoku Publication Hei-1-16389 discloses an adsorbent comprising polymyxin, which is known as an antidote against endotoxins, immobilized on an appropriate carrier. This adsorbent is effective against infections with gram negative bacteria but the removal of endotoxins alone cannot be expected to be highly effective against infections with gram positive bacteria or multiple infections with gram positive and gram negative bacteria.
Furthermore, in recent years, it has been revealed that TSST-1, as a superantigen, activates the immune system and enhances the endotoxin toxicity to a level thousands of times higher. Therefore, the occurrence of an endotoxin at a low concentration, at which septicemia will not be caused clinically, is indicated to cause septicemia.
Accordingly, the advent of a highly effective adsorbent for bacterial toxins, which can be produced in an inexpensive and simple and easy manner, is earnestly desired.